Recent advances in cross-coupling of alcohols via borrowing hydrogen catalysis.

Application of the borrowing hydrogen strategy facilitates utilization of abundantly available alcohols for linear or branched long-chain alcohols. Selective synthesis of such alcohols is highly challenging and involves the utilization of transition metal catalysts towards the desired cross-coupled product. Herein, we have highlighted recent advances (from 2015 to 2023) towards the synthesis of higher alcohols. Major focus has been given to the development of ligands, including transition metal catalysts. Judicious catalyst design plays a key role in the alkylation process and is summarised in this review.

Harnessing alcohols as sustainable reagents for late-stage functionalisation: synthesis of drugs and bio-inspired compounds.

Alcohol is ubiquitous with unparalleled structural diversity and thus has wide applications as a native functional group in organic synthesis. It is highly prevalent among biomolecules and offers promising opportunities for the development of chemical libraries. Over the last decade, alcohol has been extensively used as an environmentally friendly chemical for numerous organic transformations. In this review, we collectively discuss the utilisation of alcohol from 2015 to 2023 in various organic transformations and their application toward intermediates of drugs, drug derivatives and natural product-like molecules. Notable features discussed are as follows: (i) sustainable approaches for C-X alkylation (X = C, N, or O) including O-phosphorylation of alcohols, (ii) newer strategies using methanol as a methylating reagent, (iii) allylation of alkenes and alkynes including allylic trifluoromethylations, (iv) alkenylation of N-heterocycles, ketones, sulfones, and ylides towards the synthesis of drug-like molecules, (v) cyclisation and annulation to pharmaceutically active molecules, and (vi) coupling of alcohols with aryl halides or triflates, aryl cyanide and olefins to access drug-like molecules. We summarise the synthesis of over 100 drugs via several approaches, where alcohol was used as one of the potential coupling partners. Additionally, a library of molecules consisting over 60 fatty acids or steroid motifs is documented for late-stage functionalisation including the challenges and opportunities for harnessing alcohols as renewable resources.

Recent advances in the selective semi-hydrogenation of alkyne to (E)-olefins.

Considering the potential importance and upsurge in demand, the selective semi-hydrogenation of alkynes to (E)-olefins has attracted significant interest. This article highlights the recent advances in newer technologies and important methodologies directed to (E)-olefins from alkynes developed from 2015 to 2023. Notable features summarised include the catalyst or ligand design and control of product selectivity based on precious and nonprecious metal catalysts for semi-hydrogenation to (E)-olefins. Mechanistic studies for various catalytic transformations, including synthetic application to bioactive compounds, are summarised.

Recent advances on non-precious metal-catalysed fluorination, difluoromethylation, trifluoromethylation, and perfluoroalkylation of N-heteroarenes.

This review highlights the recent advances, from 2015 to 2023, on the introduction of organo-fluorine derivatives at the N-heteroarene core. Notable features considering new technologies based on organofluorine compounds such as: (i) approaches based on non-precious metal catalysis (Fe, Co, Mn, Ni, etc.), (ii) the development of new strategies using non-precious metal-catalysts for the introduction of organo-fluorinine derivatives using N-heterocycles with one or more heteroatoms, (iii) newer reagents for fluorination, difluoromethylation, trifluoromethylation, or perfluoroalkylation of N-heteroarenes using different approaches, (iv) mechanistic studies on various catalytic transformations, as and when required, and (v) the synthetic applications of various bio-active organo-fluorine compounds, including post-synthetic drug derivatization, are discussed.

Nickel-Catalyzed Alkylation of Oxindoles with Secondary Alcohols.

Herein, we have demonstrated a simple nickel-catalyzed C-3-selective alkylation of 2-oxindoles using a wide variety of secondary alkyl alcohols. As a special highlight, functionalization of the cholesterol derivative was reported. Control experiments, initial mechanistic studies, and deuterium-labeling experiments were performed for the alkylation process.

KDM6 demethylases integrate DNA repair gene regulation and loss of KDM6A sensitizes human acute myeloid leukemia to PARP and BCL2 inhibition.

Acute myeloid leukemia (AML) is a heterogeneous, aggressive malignancy with dismal prognosis and with limited availability of targeted therapies. Epigenetic deregulation contributes to AML pathogenesis. KDM6 proteins are histone-3-lysine-27-demethylases that play context-dependent roles in AML. We inform that KDM6-demethylase function critically regulates DNA-damage-repair-(DDR) gene expression in AML. Mechanistically, KDM6 expression is regulated by genotoxic stress, with deficiency of KDM6A-(UTX) and KDM6B-(JMJD3) impairing DDR transcriptional activation and compromising repair potential. Acquired KDM6A loss-of-function mutations are implicated in chemoresistance, although a significant percentage of relapsed-AML has upregulated KDM6A. Olaparib treatment reduced engraftment of KDM6A-mutant-AML-patient-derived xenografts, highlighting synthetic lethality using Poly-(ADP-ribose)-polymerase-(PARP)-inhibition. Crucially, a higher KDM6A expression is correlated with venetoclax tolerance. Loss of KDM6A increased mitochondrial activity, BCL2 expression, and sensitized AML cells to venetoclax. Additionally, BCL2A1 associates with venetoclax resistance, and KDM6A loss was accompanied with a downregulated BCL2A1. Corroborating these results, dual targeting of PARP and BCL2 was superior to PARP or BCL2 inhibitor monotherapy in inducing AML apoptosis, and primary AML cells carrying KDM6A-domain mutations were even more sensitive to the combination. Together, our study illustrates a mechanistic rationale in support of a novel combination therapy for AML based on subtype-heterogeneity, and establishes KDM6A as a molecular regulator for determining therapeutic efficacy.

Immobilizing a homogeneous manganese catalyst into MOF pores for α-alkylation of methylene ketones with alcohols.

Herein, for the first time, a metal-organic framework (MOF) is reported as a catalyst for α-alkylation of ketones with alcohols. Using an encapsulation strategy via nano-confinement of a homogeneous Mn-phenanthroline complex into MOF pores, functionalized branched ketones were selectively produced. Mechanistic investigations and deuterium labelling experiments validated the utilization of the borrowing hydrogen strategy. The formation of extra Lewis acid sites, defects, and pore enhancement during catalysis helped in achieving higher activity and selectivity.

Effects of tyrosine kinase inhibitors for controlling Ph+ clone and additional clonal abnormalities in a chronic myeloid leukemia.

Purpose: The chronic myeloid leukemia (CML) is characterized by the presence of t(9;22)(q34;q11) that results in chimerization of BCR and ABL genes on the rearranged chromosome 22 or Philadelphia chromosome (Ph). Imatinib has been established as the first line of therapy for CML; in case of Imatinib failure or resistance, other second or third generation tyrosine kinase inhibitors (TKIs) are considered. However, acquisition of additional clonal abnormalities (ACAs) interferes in management of CML. We described a complex scenario of cytogenetic remission, relapse, response to TKIs and behavior of ACAs in a case of CML. Materials and Methods: Conventional G-banding and FISH cytogenetics, and quantitative PCR studies were conducted in the bone marrow for diagnosis and follow up (FU) of the changes of BCR-ABL gene and ACAs at different time intervals. Results: Ph- chromosome disappeared within 6 months of Imatinib therapy, and re-appeared within a year. Subsequent change of TKI to dasatinib eliminated the Ph+ clone, but established an ACA with trisomy 8 (+8). Further change to Nilotinib, eliminated +8 clone, but re-emergence of Ph+ clone occurred with an ACA with monosomy 7 (-7). Reinstate of Dasatinib eliminated Ph+ and -7 clones, but with gradual reappearance of Ph+ and +8 clones. The patient discontinued FU, though participated in a long term examination. Conclusion: The complexity of ACAs and Ph+ clones needs frequent monitoring with changes of TKI and technologies.

Recent advances on non-precious metal-catalyzed C-H functionalization of N-heteroarenes.

N-Heteroarenes are widely used for numerous medicinal applications, lifesaving drugs and show utmost importance as intermediates in chemical synthesis. This feature article highlights the recent advances, from 2015 to August 2021, on sp2 and sp3 C-H bond functionalization reactions of various N-heteroarenes catalyzed by non-precious transition metals (Mn, Co, Fe, Ni, etc.). The salient features of the report are: (i) the development of newer catalysis for Csp2-H activation of N-heteroarenes and categorized into alkylation, alkenylation, borylation, cyanation, and annulation reactions, (ii) recent advances on Csp3-H bond functionalization of N-heteroarenes considering newer approaches for alkylation as well as alkenylation processes, and (iii) synthetic applications and practical utility of the catalytic protocols utilized for late-stage drug development; (iv) scope for the development of newer catalytic protocols along with mechanistic studies and detail mechanistic findings of various important processes.

Recent advances in the synthesis of N-heteroarenes via catalytic dehydrogenation of N-heterocycles.

Bio-active molecules having N-heteroarene core are widely used for numerous medicinal applications and as lifesaving drugs. In this direction, dehydrogenation of partially saturated aromatic N-heterocycles shows utmost importance for the synthesis of heterocycles. This feature article highlights the recent advances, from 2009 to April 2021, on the dehydrogenation of N-heteroaromatics. Notable features considering the development of newer catalysis for dehydrogenations are: (i) approaches based on precious metal catalysis, (ii) newer strategies and catalyst development technology using non-precious metal-catalysts for N-heterocycles having one or more heteroatoms, (iii) Synthesis of five or six-membered N-heterocycles using photocatalysis, electrocatalytic, and organo-catalytic approaches using different homogeneous and heterogeneous conditions' (iv) metal free (base and acid-promoted) dehydrogenation along with I2, N-hydroxyphthalimide (NHPI) and bio catalyzed miscellaneous examples have also been discussed, (v) mechanistic studies for various dehydrogenation reactions and (vi) synthetic applications of various bio-active molecules including post-drug derivatization are discussed.

Heterogenizing a Homogeneous Nickel Catalyst Using Nanoconfined Strategy for Selective Synthesis of Mono- and 1,2-Disubstituted Benzimidazoles.

A homogeneous Ni-phenanthroline catalyst was successfully immobilized into the cavities of a metal-organic framework, ZIF-8. The as-synthesized heterogeneous catalyst, Ni-Phen@ZIF, represents the first MOF based catalyst that enables dehydrogenative coupling of alcohols with aromatic diamines for selective synthesis of both mono- and 1,2-disubstituted benzimidazoles. The catalyst survived under harsh basic conditions, characterized by SEM, TEM, BET, PXRD, and EDX elemental mappings. The presence of the nanoconfined Ni-phenanthroline complex and the formation of extra Lewis acid sites during catalysis in the Ni-Phen@ZIF structure, confirmed by TPD analysis and kinetic experiments, might be responsible for higher activity and selectivity.

Recent advances in transition metal-catalyzed (1,n) annulation using (de)-hydrogenative coupling with alcohols.

(1,n) annulation reactions using (de)-hydrogenative coupling with alcohols or diols represent a straightforward technique for the synthesis of cyclic moieties. Utilization of such renewable resources for chemical transformations in a one-pot manner is the main focus, which avoids generation of stoichiometric waste. Application of such (1,n) annulation approaches drives the catalysis research in a more sustainable way and generates dihydrogen and water as by-products. This feature article highlights the recent (from 2015 to March 2021) progress in the synthesis of stereo-selective cycloalkanes and cycloalkenes, saturated and unsaturated N-heterocycles (cyclic amine, imide, lactam, tetrahydro ß-carboline, quinazoline, quinazolinone, 1,3,5-triazines etc.) and other N-heterocycles with the formation of multiple bonds in a one pot operation. Mechanistic studies, new catalytic approaches, and synthetic applications including drug synthesis and post-drug derivatization, scope, and limitations are discussed.

Nickel-Catalyzed Dehydrogenation of N-Heterocycles Using Molecular Oxygen.

Herein, an efficient and selective nickel-catalyzed dehydrogenation of five- and six-membered N-heterocycles is presented. The transformation occurs in the presence of alkyl, alkoxy, chloro, free hydroxyl and primary amine, internal and terminal olefin, trifluoromethyl, and ester functional groups. Synthesis of an important ligand and the antimalarial drug quinine is demonstrated. Mechanistic studies revealed that the cyclic imine serves as the key intermediate for this stepwise transformation.

Nickel-catalyzed hydrogen-borrowing strategy: chemo-selective alkylation of nitriles with alcohols.

The first nickel-catalyzed hydrogen-borrowing alkylation of a series of aryl acetonitriles with a variety of aryl, heteroaryl, allylic and alkyl alcohols releasing water as the by-product (>33 examples, up to 90% yield) is reported.

Iron-catalysed alkylation of 2-methyl and 4-methyl azaarenes with alcohols via C-H bond activation.

The first Fe-catalysed alkylation of 2-methyl and 4-methyl-azaarenes with a series of alkyl and hetero-aryl alcohols is reported (>39 examples and up to 95% yield). Multi-functionalisation of pyrazines and synthesis of anti-malarial drug (±) Angustureine significantly broaden the scope of this methodology. Preliminary mechanistic investigation, deuterium labeling and kinetic experiments including trapping of the enamine intermediate 1a' are of special importance.

A Simple Iron-Catalyst for Alkenylation of Ketones Using Primary Alcohols.

Herein, we developed a simple iron-catalyzed system for the α-alkenylation of ketones using primary alcohols. Such acceptor-less dehydrogenative coupling (ADC) of alcohols resulted in the synthesis of a series of important α,ß-unsaturated functionalized ketones, having aryl, heteroaryl, alkyl, nitro, nitrile and trifluoro-methyl, as well as halogen moieties, with excellent yields and selectivity. Initial mechanistic studies, including deuterium labeling experiments, determination of rate and order of the reaction, and quantitative determination of H2 gas, were performed. The overall transformations produce water and dihydrogen as byproducts.

Nickel-Catalyzed Double Dehydrogenative Coupling of Secondary Alcohols and ß-Amino Alcohols To Access Substituted Pyrroles.

Herein, we demonstrate the first nickel-catalyzed double dehydrogenative condensation of secondary alcohols and ß-amino alcohols in one pot to the pyrrole derivatives. A series of 2,5- and 2,3,5-substituted pyrroles were obtained in ≤83% yield, releasing water and hydrogen gas as byproducts. Initial mechanistic studies, including defined Ni catalyst, deuterium labeling experiments, quantitative determination of hydrogen gas evaluation, and detection of water generation in the reaction mixture, were performed.

Iron-Catalyzed Coupling of Methyl N-Heteroarenes with Primary Alcohols: Direct Access to E-Selective Olefins.

An efficient Fe-catalyzed system is reported for direct α-olefination of methyl-substituted N-heteroarenes with primary alcohols. The catalytic dehydrogenative coupling enables a series of functionalized E-olefinated N-heteroaromatics with excellent selectivity (>99%). Initial mechanistic studies including deuterium-labeling experiments provide evidence for the participation of the benzylic C-H/D bond of alcohols.

Iron-Catalyzed Ligand Free α-Alkylation of Methylene Ketones and ß-Alkylation of Secondary Alcohols Using Primary Alcohols.

Herein, we demonstrate a general and broadly applicable catalytic cross coupling of methylene ketones and secondary alcohols with a series of primary alcohols to disubstituted branched ketones. A simple and nonprecious Fe2(CO)9 catalyst enables one-pot oxidations of both primary and secondary alcohols to a range of branched gem-bis(alkyl) ketones. A number of bond activations and formations selectively occurred in one pot to provide the ketone products. Coupling reactions can be performed in gram scale and successfully applied in the synthesis of an Alzehimer's drug. Alkylation of a steroid hormone can be achieved. A single catalyst enables sequential one-pot double alkylation to bis-hetero aryl ketones using two different alcohols. Preliminary mechanistic studies using an IR probe, deuterium labeling, and kinetic experiments established the participation of a borrowing-hydrogen process using Fe catalyst, and the reaction produces H2 and H2O as byproducts.

Nickel-catalysed direct α-olefination of alkyl substituted N-heteroarenes with alcohols.

Catalytic α-olefination of alkylheteroarenes with primary alcohols via dehydrogenative coupling is presented. A simple nickel catalyst system stabilised by readily available nitrogen ligands enables a series of interesting E-configured vinylarenes (confirmed by X-ray crystal-structure analysis) to be synthesised in good to excellent yields with olefin/alkane selectivity of >20 : 1. Hydrogen and water are generated as byproducts and quantitative determination of H2 was performed.